Understanding how learning and memory are modulated is an important aspect of understanding how memories are formed. Emotional state, various environmental factors, and diseases of the nervous system can impact the formation of memory. The long-term goals of our research are to define factors that normally modulate memory formation and to determine how these factors modulate learning and memory. In addressing these goals, we discovered that the circadian clock modulates a simple form of long-term memory, long-term sensitization of the tail-siphon withdrawal reflex in Aplysia. Animals form long-term memory when they are trained during the day but form much less memory when they are trained at night. However, short-term memory of the same behavior is formed equally well during the day and night. The Specific Aims extend our previous research by investigating circadian modulation of other forms of memory and the mechanisms responsible for circadian modulation of long-term memory. Specific Aim 1 is to determine the scope and function of circadian modulation of learning and memory. We will investigate circadian modulation of a more complex associative form of learning (learning that food is inedible), and we will investigate circadian modulation of learning in nocturnal species of Aplysia. Specific Aim 2 is to determine the circuitry involved in the circadian modulation of learning and memory. We will investigate the role of the circadian pacemaker in the eye, and we will determine whether circadian modulation of memory persists in a semi-intact preparation. Specific Aim 3 is to determine whether the circadian clock modulates learning and memory through modulation of facilitatory serotonergic neurons in the learning and memory circuitry. We will investigate whether circadian modulation of release of serotonin is responsible for the modulation of memory formation. Specific Aim 4 is to determine which biochemical and molecular events necessary for the induction of long-term memory in sensory neurons are responsible for the circadian modulation of memory. We will investigate circadian modulation of synthesis of ApC/EBP mRNA and activation of MAPK and PKA during the formation of memory. In addition to elucidating the modulation of learning and memory, this research will provide insights into how the circadian clock regulates its outputs to produce rhythms. Furthermore, knowing the mechanisms by which memory formation is modulated will aid attempts to improve memory as well as to treat diseases that affect memory.